Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines
Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines
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DOI：
10.1038/labinvest.2008.19
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发表时间：
2008-05-01
影响因子：
5
通讯作者：
Reis-Filho, Jorge S.
中科院分区：
文献类型：
--
作者：
Arriola, Edurne;Marchio, Caterina;Reis-Filho, Jorge S.
HER 2和TOP 2A是治疗剂曲妥珠单抗和蒽环类药物的靶标，并且在乳腺癌中经常扩增。本研究的目的是提供携带HER 2/TOP 2A共扩增的乳腺癌中17 q12-q21扩增子的详细分子遗传学分析，并研究HER 2/TOP 2A共扩增癌症中的其他复发性共扩增。总共对15种具有HER 2扩增的乳腺癌（其中10种还具有TOP 2A扩增，如通过显色原位杂交所定义）和6种已知扩增HER 2的乳腺癌细胞系进行基于高分辨率微阵列的比较基因组杂交分析。这表明，12例病例的基因组的特征是至少有一个局部区域的集群，相对狭窄的扩增峰，每个集群局限于一个单一的染色体臂（即“火风暴”模式）和3例显示许多狭窄的重复和缺失片段，影响绝大多数染色体（即“火风暴”模式）。在整个系列中，17 q12上的最小扩增区域（SRA）从34.73延伸到35.48 Mb，并且包括HER 2而不包括TOP 2A。在HER 2/TOP 2A共扩增样本中，SRA从34.73 Mb延伸至36.54 Mb，跨越B1.8 Mb的区域。除了HER 2和T0 P2 A之外，该区域还包括另外四个基因，其表达水平在HER 2/T0 P2 A共扩增的乳腺癌中显著高于HER 2扩增的乳腺癌：CASC 3、CDC 6、RARA和SMARCE 1，如通过定量实时PCR所定义的。在研究的细胞系中，SKBR 3和UACC 812显示HER 2/TOP 2A共扩增。总之，这是HER 2/TOP 2A扩增的乳腺癌的第一个详细的全基因组表征;鉴定了可用于体外模拟这些癌症的细胞系。17 q12扩增子是复杂的，并且含有可能与乳腺癌发展和进展相关的多个基因，并且可能可用作治疗靶点。
HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A- co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray- based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes ( ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of B1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A- co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A- amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.